Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril as shown in the following formula (1), which exhibits high inhibitory action for platelet aggregation as well as inhibitory action for phosphodiesterase, antiulcer activity, hypotensive action, antiphlogistic action, etc. (Patent Reference 1) and thereby is widely used in clinical use as a drug for treating various ischemic symptoms caused by chronic arterial occlusion such as ulcer, pain and coldness. And, cilostazol has been additionally approved as a medicament having an indication which prevents the relapse after treatment of cerebral infarction (except cardiogenic cerebral infarction).
The cilostazol tablets which are called Pletaal® OD tablets 50′, Pletaal® OD tablets 100′, and Pletaal® powder 20% (OTSUKA PHARMACEUTICAL CO., LTD.) have already been on sale.

Usually, cilostazol is orally administered twice a day for an adult, but it has been desired to develop a new sustained-release formulation of cilostazol which can be absorbed in an intestinal track slowly but for a long time even by one administration, because the main subject of the drug is an elderly patient and it has been necessary to reduce the development of side effects such as headache. In addition, it has been also desired that a new formulation of cilostazol which is little affected by a food because cilostazol is susceptible to a food, for example, the Cmax and AUC of cilostazol administered after meal are 2.3 and 1.4 times higher than those of fasting, respectively.
For the purpose of developing such a sustained-release formulation, there have been a variety of studies to improve the release control and absorption of the poorly-soluble drug, cilostazol in lower gastrointestinal tract (Patent References 2 to 5).
In order to improve the dissolution and absorption of a poorly-soluble drug, in general, various means such as a micronization (nano-particulation), a solubilization with surfactants and oil, and also a solid dispersion method are used.
The solid dispersion method is carried out by dispersing a drug in an inert excipient, in many instances, a drug exists in an amorphous state in the solid dispersion. Thus, the solid dispersion method is often used as an initial method to make an amorphous drug. As a process of preparing a solid dispersion, some methods are known, for example, coprecipitating method, spray drying method, hot-melt method, and hot-melt extrusion method. For a skilled person, the most-used method among them is spray drying method, but the other methods are seldom used.
Patent Reference 6 discloses that a poorly-soluble compound is dispersed in a water-insoluble ionic polymer such as Eudragit® so that a powder of a poorly-soluble compound can be stabilized as an amorphous material. And, Patent Reference 7 discloses a process of preparing a solid dispersion comprising an amorphous compound by coprecipitating or hot-melt extruding a very insoluble imidazolidine derivative referred to as HEP with hypromellose acetate succinate (HPMC-AS).
In general, a compound in an amorphous state is unstable toward water. In particular, a high crystallinity compound in an amorphous state is unstable, which is known to be easily crystallized by the absorption of moisture or by being suspended with water. Thus, it is a big challenge to inhibit the crystallization of a formulation containing such an amorphous compound in a body, in case that the formulation is, for example, a sustained release formulation which stays in a gastrointestinal tract for long time after oral administration.
Cilostazol has an extremely low solubility in water, and has a high crystallinity, thereby it was very difficult to prepare a solid dispersion comprising a stable amorphous cilostazol. Even though a solid dispersion comprising an amorphous cilostazol can be successfully prepared through some effort of process or formula, cilostazol will easily crystallize when suspended in water. Thus, it was very difficult to apply an amorphous cilostazol to a sustained release formulation which contacts to water for a long time.